Dopamine Transporter Deficiency Syndrome (DTDS)
Disease Characteristics: DTDS is a rare, autosomal recessive childhood neurological disorder with significant disease burden, characterised by a severe parkinsonian movement disorder. DTDS results from biallelic mutations in the SLC6A3 which encodes the dopamine transporter (DAT), a key protein regulating dopaminergic signalling. Dopamine re-uptake by DAT is the principal mechanism by which dopamine is removed and recycled from synapses. Mutations in SLC6A3 result in DAT dysfunction and major dysregulation of dopamine neurotransmission, leading to hyperkinetic movement disorders in the early stages of the disease, and then evolution of parkinsonism-like features (slowing of voluntary movements, loss of facial expression, tremor, stiffness) and eye movement disorders such as oculogyric crises. The disease is often fatal in childhood to teenage years due to unexplained death in sleep or respiratory failure.
Unmet Need: There are currently no disease-modifying treatments or approved therapies for DTDS, and patients derive little clinical benefit from available symptom control medications.
Epidemiology: The disease is currently poorly diagnosed, due to symptoms similarity with other movement disorders including cerebral palsy, and the number of patients with the condition is unknown.
Program status
BGT-DTDS has demonstrated dose-dependent rescue of motor phenotype, neurodegeneration and survival in a DTDS mouse model, in both short-term and long-term studies. Following a successful Scientific Advice meeting with the UK Medicines and Healthcare products Regulatory Agency (MHRA), based upon our preclinical efficacy data and on precedents from other intra-parenchymal AAV2 gene therapies, the MHRA confirmed that it was supportive of the initiation of a clinical trial for BGT-DTDS in the UK without the need for further non-clinical studies. Subject to completing a GMP manufacturing campaign, we intend to submit a combined Clinical Trial and Ethics Committee application for a single, Phase 1/2/3 registrational clinical trial to the MHRA in 2024.
BGT-DTDS has received Orphan Drug Designation from the European Commission (EC) and the U.S. Food and Drug Administration (FDA) as well as Rare Pediatric Disease Designation (RPDD) from the FDA for the treatment of DTDS.
We are also exploring the application of the same gene therapy vector encoding for the DAT protein used in BGT-DTDS in our BGT-PD program which is targeting the treatment of Parkinson’s disease. Find out more about BGT-PD.
BGT-DTDS publications
Ng J, Barral S, De La Fuente Barrigon C, et al. Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism. Sci Transl Med. 2021;13(594):eaaw1564. doi:10.1126/scitranslmed.aaw1564
Other relevant publications
Su X, Kells AP, Salegio EA, et al. Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors [published correction appears in Mol Ther. 2012 Feb;20(2):468. Salegio, Ernesto Aguilar [corrected to Salegio, Ernesto A]]. Mol Ther. 2010;18(8):1490-1495. doi:10.1038/mt.2010.114
Kurian MA, Li Y, Zhen J, et al. Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. Lancet Neurol. 2011;10(1):54-62. doi:10.1016/S1474-4422(10)70269-6
San Sebastian W, Kells AP, Bringas J, et al. SAFETY AND TOLERABILITY OF MRI-GUIDED INFUSION OF AAV2-hAADC INTO THE MID-BRAIN OF NON-HUMAN PRIMATE. Mol Ther Methods Clin Dev. 2014;3:14049-. doi:10.1038/mtm.2014.49
Lonser RR, Akhter AS, Zabek M, Elder JB, Bankiewicz KS. Direct convective delivery of adeno-associated virus gene therapy for treatment of neurological disorders. J Neurosurg. 2020;134(6):1751-1763. Published 2020 Jul 10. doi:10.3171/2020.4.JNS20701
Pearson TS, Gupta N, San Sebastian W, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. Nat Commun. 2021;12(1):4251. Published 2021 Jul 12. doi:10.1038/s41467-021-24524-8
Ng J, Barral S, Waddington SN, Kurian MA. Dopamine Transporter Deficiency Syndrome (DTDS): Expanding the Clinical Phenotype and Precision Medicine Approaches. Cells. 2023; 12(13):1737. https://doi.org/10.3390/cells12131737
More information about DTDS
DTDS Foundation https://dtdsfoundation.org/
